Skip to content
TriangleGet started
← Study library

NCT01072175 · CITED IN SOURCE DOCUMENTS

Investigate Safety, Pharmacokinetics and Pharmacodynamics of GSK2118436 & GSK1120212

An NCI or FDA source cites this study. A citation does not establish that it applies to an individual diagnosis.

Phase
PHASE2
Status at capture
COMPLETED
Registry last update
2019-07-05

This was an open-label, dose escalation study to investigate the safety, pharmacokinetics, pharmacodynamics and clinical activity of GSK2118436 and GSK1120212 in combination. This study was designed in four parts. In Part A, the effect of repeat doses of GSK1120212 on the pharmacokinetics of single dose GSK2118436 was investigated prior to evaluating combination regimens. In Part B, the range of tolerated dose combinations was identified using a dose-escalation procedure. In Part C, different dose combinations of GSK2118436 and GSK1120212 were evaluated, based on results from the dose escalation cohorts. In Part D, the pharmacokinetics and safety of GSK2118436 administered as HPMC capsules alone and in combination with GSK1120212 was evaluated.

Open the original ClinicalTrials.gov record → · Download preserved record

What did the study report?

Outcomes, safety and baseline populations are separate source sections. Quality-of-life measures appear under their original outcome titles.

flow

Participant flow

→

baseline

Baseline characteristics

→

outcome · POSTED

Part A: Maximum Plasma Concentration (Cmax) of a Single Dose of Dabrafenib Administered Alone and in Combination With Trametnib

→

outcome · POSTED

Part A: AUC (0-t) and AUC (0-inf) of Dabrafenib and Its Metabolites

→

outcome · POSTED

Part B: Number of Participants With Any Adverse Event (AE) or Serious Adverse Event (SAE)

→

outcome · POSTED

Part B: Number of Participants With Worst-case Chemistry Toxicity Grade Change From Baseline

→

outcome · POSTED

Part B: Number of Participants With Worst-case Chemistry Change From Baseline With Respect to Normal Range

→

outcome · POSTED

Part B: Number of Participants With Worst-case Hematology Toxicity Grade Change From Baseline

→

outcome · POSTED

Part B: Number of Participants With Worst-case Hematology Change From Baseline With Respect to Normal Range

→

outcome · POSTED

Part B: Number of Participants With the Indicated Worst-case Change From Baseline in Heart Rate and Blood Pressure

→

outcome · POSTED

Part C (Randomized): Number of Participants With BRAF Mutant Metastatic Melanoma With Best Overall Response as Assessed by the Investigator

→

outcome · POSTED

Part C (Randomized): Number of Participants With BRAF Mutant Metastatic Melanoma With Best Overall Response Assessed by Blinded Independent Central Review (BICR)

→

outcome · POSTED

Part C (Crossover): Number of Participants With BRAF Mutant Metastatic Melanoma With Best Overall Response as Assessed by the Investigator

→

outcome · POSTED

Part C (Randomized): Progression-free Survival (PFS) as Assessed by the Investigator

→

outcome · POSTED

Part C (Crossover): Progression-free Survival (PFS) as Assessed by the Investigator

→

outcome · POSTED

Part C (Randomized): Progression-free Survival (PFS) as Assessed by the Blinded Independent Central Review (BICR)

→

outcome · POSTED

Part C (Randomized): Duration of Response as Assessed by the Investigator and Blinded Independent Central Review (BICR)

→

outcome · POSTED

Part C (Randomized): Number of Participants With Any Adverse Event (AE) or Serious Adverse Event (SAE)

→

outcome · POSTED

Part C (Randomized): Number of Participants With Worst-case Chemistry Toxicity Grade Change From Baseline

→

outcome · POSTED

Part C (Randomized): Number of Participants With Worst-case Chemistry Change From Baseline With Respect to Normal Range

→

outcome · POSTED

Part C (Randomized): Number of Participants With Worst-case Hematology Toxicity Grade Change From Baseline

→

outcome · POSTED

Part C (Randomized): Number of Participants With Worst-case Hematology Change From Baseline With Respect to Normal Range

→

outcome · POSTED

Part C (Randomized): Number of Participants With the Indicated Worst-case Change From Baseline in Heart Rate and Blood Pressure

→

outcome · POSTED

Part D (Analyte=GSK2118436): Maximum Plasma Concentration (Cmax) of a Single and Repeat Dose of Dabrafenib Alone and in Combination With Trametinib

→

outcome · POSTED

Part D (Analyte=GSK2118436): Tmax of a Single and Repeat Dose of Dabrafenib Alone and in Combination With Trametinib

→

outcome · POSTED

Part D (Analyte=GSK2118436): AUC (0-tau) and AUC (0-inf) of Single and Repeat Doses of Dabrafenib Alone and in Combination With Trametinib

→

outcome · POSTED

Part D: Number of Participants With Any Adverse Event (AE) or Serious Adverse Event (SAE)

→

outcome · POSTED

Part D: Number of Participants With Worst-case Chemistry Toxicity Grade Change From Baseline

→

outcome · POSTED

Part D: Number of Participants With Worst-case Chemistry Change From Baseline With Respect to Normal Range

→

outcome · POSTED

Part D: Number of Participants With Worst-case Hematology Toxicity Grade Change From Baseline

→

outcome · POSTED

Part D: Number of Participants With Worst-case Hematology Change From Baseline With Respect to Normal Range

→

outcome · POSTED

Part D: Number of Participants With the Indicated Worst-case Change From Baseline in Heart Rate and Blood Pressure

→

outcome · POSTED

Part A: Steady State Concentration of Trametinib With Concomitant Administration of Dabrafenib

→

outcome · POSTED

Part B: AUC [0-tau] of Dabrafenib (DAB) and Its Metabolite in Combination With Trametinib

→

outcome · POSTED

Part B: Pre-dose (Trough) Concentration at the End of the Dosing Interval (Ctau) and Maximum Plasma Concentration (Cmax) of Dabrafenib and Its Metabolite in Combination With Trametinib

→

outcome · POSTED

Part B: Tmax of Dabrafenib and Its Metabolite in Combination With Trametinib

→

outcome · POSTED

Part B (Analyte=GSK1120212): AUC (0-tau) Assessment of Trametinib in Combination With Dabrafenib

→

outcome · POSTED

Part B (Analyte=GSK1120212): Ctau and Cmax Assessments of Trametinib in Combination With Dabrafenib

→

outcome · POSTED

Part B (Analyte=GSK1120212): Tmax Assessment of Trametinib in Combination With Dabrafenib

→

outcome · POSTED

Part B: Number of Participants With BRAFi-naïve Mutant Metastatic Melanoma With the Best Overall Response as Assessed by Investigator

→

outcome · POSTED

Part B: Duration of Response as Assessed by the Investigator in Participants With BRAFi-naïve Mutant Metastatic Melanoma

→

outcome · POSTED

Part B: Progression-free Survival (PFS) as Assessed by the Investigator in Participants With BRAFi-naïve Mutant Metastatic Melanoma

→

outcome · POSTED

Part B: Overall Survival (OS) in BRAFi Naïve Melanoma Participants

→

outcome · POSTED

Part B: Pre- and Post-dose H-scores for Individual Participants

→

outcome · POSTED

Part C (Randomized): Overall Survival (OS)

→

outcome · POSTED

Part C: Plasma Concentrations of Dabrafenib and Its Metabolites

→

outcome · POSTED

Part C: Plasma Concentrations of Trametinib

→

outcome · POSTED

Part C: Oral Clearance (CL/F) of Dabrafenib and Trametinib

→

outcome · POSTED

Part C: Oral Volume of Distribution (V/F) of Dabrafenib and Trametinib

→

outcome · POSTED

Part D: Cmax of Dabrafenib Metabolites

→

outcome · POSTED

Part D: Tmax of Dabrafenib Metabolites

→

outcome · POSTED

Part D: Area Under the Concentration-time Curve (AUC) of Dabrafenib Metabolites

→

outcome · POSTED

Part D: Cmax Assessment of Trametinib

→

outcome · POSTED

Part D: Tmax Assessment of Trametinib

→

outcome · POSTED

Part D: Area Under the Concentration-time Curve Assessment of Trametinib

→

outcome · POSTED

Part D: Number of Participants With the Best Overall Response as Assessed by the Investigator in Participants

→

outcome · POSTED

Part D: Duration of Response as Assessed by the Investigator

→

outcome · POSTED

Part D: Progression-free Survival (PFS) as Assessed by the Investigator

→

outcome · POSTED

Part D: Overall Survival (OS)

→

adverse events

Adverse events

→

more info

Limitations, agreements, and source contact

→
Who could take part
eligibility Criteria
Key Inclusion Criteria: * Capable of given written informed consent, which includes compliance with the requirements and restrictions listed in the consent form. * Male or female age 18 years or greater; able to swallow and retain oral medication. * BRAF mutation positive melanoma or colorectal cancer; other BRAF mutation positive tumor types may be considered. * Measurable disease according to RECIST version 1.1. * Eastern Cooperative Oncology Group Performance Status of 0 or 1 for Parts A and B. Subjects with Eastern Cooperative Oncology Group Performance Status of 2 or less may be entered into Part C with approval of medical monitor. * Agree to contraception requirements. * Calcium phosphorus product less than 4.0mmol2/L2. * Adequate organ system function. Key Exclusion Criteria: * Currently receiving cancer therapy (chemotherapy, radiation therapy, immunotherapy, or biologic therapy). * Part A and Part B: Prior exposure to BRAF or MEK inhibitors unless approved by the GSK Medical Monitor. * Part C: Prior exposure to BRAF or MEK inhibitors. Prior anti-cancer therapy in the metastatic setting, with the exception of up to one regimen of chemotherapy and/or interleukin-2 (IL-2). * Part D: Prior exposure to BRAF inhibitors. A washout period of 6 weeks is required for ipilimumab. * Received an investigational anti-cancer drug within 4 weeks or 5 half-lives (whichever is shorter) of study drug administration--- at least 14 days must have passed between the last dose of prior investigational anti-cancer drug and the first dose of study drug. * Current use of a prohibited medication or requires any of these medications during treatment with study drug. * Current use of therapeutic warfarin. * Any major surgery, radiotherapy, or immunotherapy within the last 4 weeks. Limited radiotherapy within the last 2 weeks. * Chemotherapy regimens with delayed toxicity within the last 4 weeks. Chemotherapy regimens given continuously or on a weekly basis with limited potential for delayed toxicity within the last 2 weeks. * Unresolved toxicity greater than National Cancer Institute-Common Terminology Criteria for Adverse Events version 4 Grade 1 from previous anti-cancer therapy except alopecia. * History of retinal vein occlusion, central serous retinopathy or glaucoma. * Predisposing factors to retinal vein occlusion including uncontrolled hypertension, uncontrolled diabetes, uncontrolled hyperlipidemia, and coagulopathy. * Visible retinal pathology as assessed by ophthalmologic exam that is considered a risk factor for retinal vein occlusion or central serous retinopathy. * Intraocular pressure greater than 21mm Hg as measured by tonography. * Glaucoma diagnosed within one month prior to study Day 1. * Presence of active gastrointestinal disease or other condition that will interfere significantly with the absorption, distribution, metabolism or excretion of drugs. * Known human immunodeficiency virus, Hepatitis B or Hepatitis C infection. * Primary malignancy of the central nervous system. * Untreated or symptomatic brain metastasis, leptomeningeal disease or spinal cord compression. Subjects who are on a stable dose of corticosteroids for more than 1 month or off corticosteroids for 2 weeks can be enrolled with approval of medical monitor. Subjects are not permitted to receive enzyme-inducing anti-epileptic drugs. * Subjects with brain metastases are excluded, unless a. All known lesions must be previously treated with surgery or stereotactic radiosurgery, and- b. Brain lesion(s), if still present, must be confirmed stable (i.e. no increase in lesion size) for ≥90 days prior to first dose on study (must be documented with two consecutive MRI or CT scans using contrast), and c. Asymptomatic with no corticosteroids requirement for ≥ 30 days prior to first dose on study, and d. No enzyme-inducing anticonvulsants for ≥ 30 days prior to first dose on study. * History of alcohol or drug abuse within 6 months prior to screening. * Psychological, familial, sociological or geographical conditions that do not permit compliance with the protocol. * QTc interval greater than or equal to 480msecs. * History of acute coronary syndromes (including unstable angina), coronary angioplasty, or stenting within the past 24 weeks. * Class II, III, or IV heart failure as defined by the New York Heart Association functional classification system. * Abnormal cardiac valve morphology (subjects with minimal abnormalities can be entered on study with approval from the medical monitor. * Treatment refractory hypertension defined as a blood pressure of systolic\> 140 mmHg and/or diastolic \> 90 mm Hg which cannot be controlled by anti-hypertensive therapy * Patients with intra-cardiac defibrillators or permanent pacemakers. * Cardiac metastases * Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to the study drugs or excipients. * Pregnant or lactating female. * Unwillingness or inability to follow the procedures required in the protocol. * Uncontrolled diabetes, hypertension or other medical conditions that may interfere with assessment of toxicity. * Subjects with known glucose 6 phosphate dehydrogenase deficiency.
healthy Volunteers
false
minimum Age
18 Years
sex
ALL
std Ages
  1. ADULT
  2. OLDER_ADULT
Treatment arms and interventions
arm Groups
  1. description
    Day 1: GSK2118436 75mg; Day 2 through Day 16: GSK1120212 2mg; Day 15: GSK2118436 75mg +GSK1120212 2mg Drug-drug interaction
    intervention Names
    1. Drug: GSK2118436
    2. Drug: GSK1120212
    label
    Arm Part A
    type
    EXPERIMENTAL
  2. description
    GSK2118436 + GSK1120212 Dose escalation to a maximum tolerated combination dose
    intervention Names
    1. Drug: GSK2118436
    label
    Arm Part B
    type
    EXPERIMENTAL
  3. description
    GSK2118436 + GSK1120212 cohort expansion for safety and efficacy
    intervention Names
    1. Drug: GSK2118436
    2. Drug: GSK1120212
    label
    Arm Part C
    type
    EXPERIMENTAL
interventions
  1. arm Group Labels
    1. Arm Part A
    2. Arm Part B
    3. Arm Part C
    description
    GSK2118436 is a potent and selective inhibitor of BRAF kinase activity with a mode of action consistent with adenosine triphosphate-competitive inhibition.
    name
    GSK2118436
    type
    DRUG
  2. arm Group Labels
    1. Arm Part A
    2. Arm Part C
    description
    GSK1120212 is a potent and highly selective inhibitor of MEK1/2 activation and kinase activity.
    name
    GSK1120212
    type
    DRUG
Study design
allocation
NON_RANDOMIZED
masking Info
masking
NONE
primary Purpose
TREATMENT
Enrollment
count
430
type
ACTUAL
Registered outcome plans (not posted results)
primary Outcomes
  1. description
    Blood samples for PK analysis of dabrafenib and its the metabolites hydroxy-dabrafenib (GSK2285403), carboxy-dabrafenib (GSK2298683) and desmethyl-dabrafenib (GSK2167542) were obtained at pre-dose and at 1, 2, 3, 4, 6, 8, 10, and 24 hours after dabrafenib administration. From the plasma concentration-time curve, the PK parameter Cmax was determined by standard non-compartmental analysis using WinNonlin. Cmax data are reported as geometric least squares means.
    measure
    Part A: Maximum Plasma Concentration (Cmax) of a Single Dose of Dabrafenib Administered Alone and in Combination With Trametnib
    time Frame
    Day 15
  2. description
    Blood samples for PK analysis of dabrafenib and its metabolites hydroxy-dabrafenib (GSK2285403), carboxy-dabrafenib (GSK2298683) and desmethyl-dabrafenib (GSK2167542) were obtained at pre-dose and at 1, 2, 3, 4, 6, 8, 10, and 24 hours after dabrafenib administration. AUC is defined as the area under the dabrafenib concentration-time curve as a measure of drug exposure. AUC (0-inf) is defined as the area under the concentration-time curve from time zero (pre-dose) extrapolated to infinite time. AUC (0-t) is defined as area under the concentration-time curve from time zero (pre-dose) to the last time of quantifiable concentration. Date are reported as geometric least square means.
    measure
    Part A: AUC (0-t) and AUC (0-inf) of Dabrafenib and Its Metabolites
    time Frame
    Day 15
  3. description
    An AE is defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, or is an event of possible drug-induced liver injury.
    measure
    Part B: Number of Participants With Any Adverse Event (AE) or Serious Adverse Event (SAE)
    time Frame
    From Baseline (Day 1) until Follow-up visit (up to approximately 8 years)
  4. description
    Clinical Chemistry parameters were summarized according to National Cancer Institutes (NCI) Common Terminology Criteria for Adverse Events (CTCAE) grade, version 4.0. Grade 1, Mild; Grade 2, Moderate; Grade 3 (G3), Severe; Grade 4 (G4), Life-threatening or disabling; Grade 5, Death. Data are presented for only those parameters for which an increase to Grade 3 or Grade 4 occurred. Participants with missing Baseline Grade were assumed to have Baseline Grade of 0. All increases were an increase in grade from Baseline. Only descriptive analysis.
    measure
    Part B: Number of Participants With Worst-case Chemistry Toxicity Grade Change From Baseline
    time Frame
    From Baseline (Day 1) until Follow-up visit (up to approximately 8 years)
  5. description
    For Clinical Chemistry parameters that were not graded according to NCI CTCAE criteria, changes above (High) and below (Low) the normal range were evaluated. Participants with missing Baseline were assumed to be within normal range. Participants were counted twice if the subject "Decreased to Low" and Increase to High" during the post-baseline period. Only descriptive analysis.
    measure
    Part B: Number of Participants With Worst-case Chemistry Change From Baseline With Respect to Normal Range
    time Frame
    From Baseline (Day 1) until Follow-up visit (up to approximately 8 years)
  6. description
    Hematology parameters were summarized according to National Cancer Institutes (NCI) Common Terminology Criteria for Adverse Events (CTCAE) grade, version 4.0. Grade 1, Mild; Grade 2, Moderate; Grade 3 (G3), Severe; Grade 4 (G4), Life-threatening or disabling; Grade 5, Death. Data are presented for only those parameters for which an increase to Grade 3 or Grade 4 occurred. Participants with missing Baseline Grade were assumed to have Baseline Grade of 0. All increases were an increase in grade from Baseline. Only descriptive analysis.
    measure
    Part B: Number of Participants With Worst-case Hematology Toxicity Grade Change From Baseline
    time Frame
    From Baseline (Day 1) until Follow-up visit (up to approximately 8 years)
  7. description
    For Hematology parameters that were not graded according to NCI CTCAE criteria, changes above (High) and below (Low) the normal range were evaluated. Participants with missing Baseline were assumed to be within normal range. Participants were counted twice if the subject "Decreased to Low" and Increase to High" during the post-baseline period. Only descriptive analysis.
    measure
    Part B: Number of Participants With Worst-case Hematology Change From Baseline With Respect to Normal Range
    time Frame
    From Baseline (Day 1) until Follow-up visit (up to approximately 8 years)
  8. description
    Blood pressure and heart rate were summarized according to NCI CTCAE grade, version 4.0. Grade 1, Mild; Grade 2, Moderate; Grade 3 (G3), Severe; Grade 4 (G4), Life-threatening or disabling; Grade 5, Death. Data are presented for only those parameters for which an increase to G3 or G4 occurred. Blood pressure measurement included systolic blood pressure (SBP, millimeters of mercury \[mmHg\]) and diastolic BP (DBP). Heart rate is the measure of heart beats per minute (bpm). Changes in heart rate, either decrease to \<60 bpm, change to normal or no change, or increase to \>100 bpm are presented.
    measure
    Part B: Number of Participants With the Indicated Worst-case Change From Baseline in Heart Rate and Blood Pressure
    time Frame
    From Baseline (Day 1) until Follow-up visit (up to approximately 8 years)
  9. description
    Best overall response is defined as complete response (CR: the disappearance of all target lesions. Any pathological lymph nodes must be \<10 millimeters \[mm\] in the short axis.) or partial reponse (PR: at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the Baseline sum of the diameters \[e.g., percent change from Baseline\]). Participants with unknown or missing responses were considered as non-responders. To be assigned a status of PR or CR, a confirmatory disease assessment should have been performed no less than 28 days after the criteria for response were first met. Response was evaluated by an investigator as per Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1.
    measure
    Part C (Randomized): Number of Participants With BRAF Mutant Metastatic Melanoma With Best Overall Response as Assessed by the Investigator
    time Frame
    From the first dose of study medication to the first documented evidence of a confirmed complete response or partial response (up to approximately 7 years)
  10. description
    Best overall response is defined as complete response (CR: the disappearance of all target lesions. Any pathological lymph nodes must be \<10 mm in the short axis.) or partial reponse (PR: at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the Baseline sum of the diameters \[e.g., percent change from Baseline\]). Participants with unknown or missing responses were considered as non-responders. To be assigned a status of PR or CR, a confirmatory disease assessment should have been performed no less than 28 days after the criteria for response were first met. Response was evaluated by BICR as per RECIST, version 1.1.
    measure
    Part C (Randomized): Number of Participants With BRAF Mutant Metastatic Melanoma With Best Overall Response Assessed by Blinded Independent Central Review (BICR)
    time Frame
    From the first dose of study medication to the first documented evidence of a confirmed complete response or partial response (up to approximately 19 months)
  11. description
    Best overall response is defined as complete response (CR: the disappearance of all target lesions. Any pathological lymph nodes must be \<10 mm in the short axis.) or partial reponse (PR: at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the Baseline sum of the diameters \[e.g., percent change from Baseline\]). Participants with unknown or missing responses were considered as non-responders. To be assigned a status of PR or CR, a confirmatory disease assessment should have been performed no less than 28 days after the criteria for response were first met. Response was evaluated by an investigator as per RECIST, version 1.1.
    measure
    Part C (Crossover): Number of Participants With BRAF Mutant Metastatic Melanoma With Best Overall Response as Assessed by the Investigator
    time Frame
    From the first dose of study medication to the first documented evidence of a confirmed complete response or partial response (up to approximately 7 years)
  12. description
    PFS is defined as the interval between the date of randomization and the earliest date of PD or death due to any cause. PD was based on radiographic or photographic evidence, and assessments were made by the investigator according to RECIST, version 1.1. PD is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as a reference, the smallest sum of diameters recorded since the treatment started (e.g., percent change from nadir, where nadir is defined as the smallest sum of diameters recorded since treatment start). In addition, the sum must have an absolute increase from nadir of 5 mm. Participants who received anti-cancer therapy prior to the date of documented events, were censored at the last adequate assessment prior to the initiation of therapy. If the participant did not had a documented date of events, PFS and survival were censored at the date of the last adequate assessment.
    measure
    Part C (Randomized): Progression-free Survival (PFS) as Assessed by the Investigator
    time Frame
    From the date of randomization to the earliest date of disease progression (PD) or death due to any cause (up to approximately 7 years)
secondary Outcomes
  1. description
    The steady state plasma concentration (Css) of trametinib with concomitant dabrafenib administration was assessed at Day 15 and Day 16. At steady state the amount of drug administered (in a given time period) is equal to the amount of drug eliminated.
    measure
    Part A: Steady State Concentration of Trametinib With Concomitant Administration of Dabrafenib
    time Frame
    Day 15 and Day 16
  2. description
    Area under the concentration-time curve from time zero (predose) until the last time of quantifiable concentration (AUC \[0-tau\]) was assessed. Blood samples for PK analysis of dabrafenib and its the metabolites hydroxy-dabrafenib (GSK2285403), carboxy-dabrafenib (GSK2298683) and desmethyl-dabrafenib (GSK2167542) were obtained at Day 15 pre-dose and Day 21 pre-dose and at 1, 2, 4, 6, and 8 hours post-dose administration.
    measure
    Part B: AUC [0-tau] of Dabrafenib (DAB) and Its Metabolite in Combination With Trametinib
    time Frame
    Day 15 and Day 21
  3. description
    Pre-dose (trough) concentration at the end of the dosing interval (Ctau) and maximum plasma concentration (Cmax) were assessed for plasma dabrafenib (DAB) following repeat dosing of DAB administered in combination with trametinib (T). The trough concentration is defined as the plasma level of a pharmaceutical product measured just before the next dose. Blood samples for PK analysis of the metabolites hydroxy-dabrafenib (GSK2285403), carboxy-dabrafenib (GSK2298683) and desmethyl-dabrafenib (GSK2167542) of dabrafenib were obtained at Day 15 pre-dose and Day 21 pre-dose and at 1, 2, 4, 6, and 8 hours post-dose administration.
    measure
    Part B: Pre-dose (Trough) Concentration at the End of the Dosing Interval (Ctau) and Maximum Plasma Concentration (Cmax) of Dabrafenib and Its Metabolite in Combination With Trametinib
    time Frame
    Day 15 and Day 21
  4. description
    The tmax is defined as the time of occurenceof Cmax. Tha tmax was assessed for plasma dabrafenib (DAB) following repeat dosing of dabrafenib 75 and 150 mg BID administered in combination with trametinib. Blood samples for PK analysis of the metabolites hydroxy-dabrafenib (GSK2285403), carboxy-dabrafenib (GSK2298683) and desmethyl-dabrafenib (GSK2167542) of dabrafenib were obtained at Day 15 pre-dose and Day 21 pre-dose and at 1, 2, 4, 6, and 8 hours post-dose administration.
    measure
    Part B: Tmax of Dabrafenib and Its Metabolite in Combination With Trametinib
    time Frame
    Day 15 and Day 21
  5. description
    AUC (0-tau) is defined as area under the concentration-time curve from time zero (pre-dose) to last time of quantifiable concentration. AUC (0-tau) was assessed for plasma trametinib following repeat dosing of trametinib in combination with dabrafenib. Blood samples for PK analysis of the metabolites of dabrafenib were obtained at Day 15 pre-dose and Day 21 pre-dose and at 1, 2, 4, 6, and 8 hours post-dose administration.
    measure
    Part B (Analyte=GSK1120212): AUC (0-tau) Assessment of Trametinib in Combination With Dabrafenib
    time Frame
    Day 15 and Day 21
  6. description
    Pre-dose (trough) concentration at the end of the dosing interval (Ctau) and maximum plasma concentration (Cmax) were assessed for plasma trametinib following repeat dosing of trametinib in combination with dabrafenib. Blood samples for PK analysis of the metabolites of dabrafenib were obtained at Day 15 pre-dose or Day 21 pre-dose and at 1, 2, 4, 6, and 8 hours post-dose administration.
    measure
    Part B (Analyte=GSK1120212): Ctau and Cmax Assessments of Trametinib in Combination With Dabrafenib
    time Frame
    Day 15 and Day 21
  7. description
    The tmax is defined as the time of occurrence of Cmax. The PK parameter for tmax was assessed for plasma trametinib following repeat dosing of trametinib in combination with dabrafenib. Blood samples for PK analysis of the metabolites of dabrafenib were obtained at Day 15 pre-dose or Day 21 pre-dose and at 1, 2, 4, 6, and 8 hours post-dose administration.
    measure
    Part B (Analyte=GSK1120212): Tmax Assessment of Trametinib in Combination With Dabrafenib
    time Frame
    Day 15 and Day 21
  8. description
    Best overall response is defined as complete response (CR: the disappearance of all target lesions. Any pathological lymph nodes must be \<10 milimeter \[mm\] in the short axis.) or partial reponse (PR: at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the Baseline sum of the diameters \[e.g., percent change from Baseline\]). Participants with unknown or missing response were considered as non-responders. To be assigned a status of PR or CR, a confirmatory disease assessment should have been performed no less than 28 days after the criteria for response were first met. Response was evaluated by an investigator as per Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. BRAFi-naïve participants were those with BRAF-mutation-positive melanoma who had not received prior therapy with a BRAF inhibitor.
    measure
    Part B: Number of Participants With BRAFi-naïve Mutant Metastatic Melanoma With the Best Overall Response as Assessed by Investigator
    time Frame
    From the first dose of study medication to the first documented evidence of a confirmed complete response or partial response (up to approximately 8 years)
  9. description
    Duration of response for participants with either a CR (the disappearance of all target lesions. Any pathological lymph nodes must be \<10 mm in the short axis.) or PR (at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the Baseline sum of the diameters \[e.g., percent change from Baseline\]) is defined as the time from the first documented evidence of a PR or CR until the first documented sign of disease progression (PD) or death due to any cause. PD is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as a reference, the smallest sum of diameters recorded since the treatment started (e.g., percent change from nadir, where nadir is defined as the smallest sum of diameters recorded since treatment start). In addition, the sum must have an absolute increase from nadir of 5 mm. BRAFi-naïve participants were those with BRAF-mutation-positive melanoma who had not received prior therapy with a BRAF inhibitor.
    measure
    Part B: Duration of Response as Assessed by the Investigator in Participants With BRAFi-naïve Mutant Metastatic Melanoma
    time Frame
    First documented evidence of PR or CR until the earlier of date of disease progression or date of death due to any cause (up to approximately 8 years)
  10. description
    PFS is defined as the interval between the first dose of study medication and the earliest date of PD or death due to any cause. PD was based on radiographic or photographic evidence, and assessments were made by the investigator according to RECIST, version 1.1. PD is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as a reference, the smallest sum of diameters recorded since the treatment started (e.g., percent change from nadir, where nadir is defined as the smallest sum of diameters recorded since treatment start). In addition, the sum must have an absolute increase from nadir of 5 mm. BRAFi-naïve were the participants with BRAF-mutation positive melanoma who had not received prior therapy with a BRAF-inhibitor..
    measure
    Part B: Progression-free Survival (PFS) as Assessed by the Investigator in Participants With BRAFi-naïve Mutant Metastatic Melanoma
    time Frame
    From the date of first dose to the earliest date of disease progression (PD) or death due to any cause (up to approximately 8 years)
  11. description
    OS is defined as the interval of time between the first dose of study medication until the date of death due to any cause. For the participants who did not die, overall survival was censored at the date of last contact.
    measure
    Part B: Overall Survival (OS) in BRAFi Naïve Melanoma Participants
    time Frame
    From the date of first dose until date of death due to any cause (up to approximately 8 years)
  12. description
    p-ERK and p-AKT, biomarkers in tumor biopsies, were assessed for participants with BRAF mutant colorectal cancer. The H-score, which is a composite score that comprises intensity and percentage of staining, is a method of assessing the amount of protein or phospho-protein present in a biopsy sample. The score is obtained by the formula: (3 \* percentage of strongly staining nuclei) + (2 \* percentage of moderately staining nuclei) + (percentage of weakly staining nuclei). The H-score ranges from 0 to 300, with a score of 0 representing the absence of any of the target protein and an H-score of 300 representing maximum staining and intensity of the target protein.
    measure
    Part B: Pre- and Post-dose H-scores for Individual Participants
    time Frame
    Screening and at disease progression (up to approximately 8 years)
Full study description
brief Summary
This was an open-label, dose escalation study to investigate the safety, pharmacokinetics, pharmacodynamics and clinical activity of GSK2118436 and GSK1120212 in combination. This study was designed in four parts. In Part A, the effect of repeat doses of GSK1120212 on the pharmacokinetics of single dose GSK2118436 was investigated prior to evaluating combination regimens. In Part B, the range of tolerated dose combinations was identified using a dose-escalation procedure. In Part C, different dose combinations of GSK2118436 and GSK1120212 were evaluated, based on results from the dose escalation cohorts. In Part D, the pharmacokinetics and safety of GSK2118436 administered as HPMC capsules alone and in combination with GSK1120212 was evaluated.
detailed Description
During Part A, a cohort of subjects received a single dose of GSK2118436 alone (Day 1) and then repeat doses of GSK1120212 for (Day 2 through Day 15). The dose regimen of GSK1120212 were continuous dosing. A second single dose of GSK2118436 was administered on Day 15 concomitantly with GSK1120212. Day 16 through Day 28 was a washout period, during which no study medication was administered. Starting on Day 29, subjects who elected to continue participation in the study were doses with GSK2118436. The dose of GSK2118436 after Day 29 might be altered based on emerging data from the first-time-in human study BRF112680. The dose might be increased to a dose level that has been completed and determined to be less than or equal to the maximum tolerated dose in that study. Part B of the study enrolled cohorts in escalating doses to identify a set of allowable doses to be expanded in Part C. Subjects were enrolled in a 3+3 cohort design, with provisional dose levels of both drugs. The decision regarding escalation to the next dose levels of GSK1120212 and GSK2118436 was further guided by a Bayesian logistic regression model. The first cohort started at low doses for both drugs. Doses up to 300 mg/day for GSK2118436 and up to 3 mg QD for GSK1120212 were studied. The starting dose might be lowered based on emerging data from other studies and from Part A. Expansion cohorts enrolled in Part C at dose levels of GSK2118436 and GSK1120212 as defined in Part B. One of the selected doses might include GSK2118436 administered as monotherapy at a tolerable dose (less than or equal to the maximum tolerated dose) determined in BRF112680. Part C was a randomized open-label Phase II portion of the study, and consisted of expansion cohorts investigating 2 to 3 dose levels of GSK2118436 and GSK1120212 dosing in combination, and GSK2118436 administered as monotherapy. Subjects were assigned to treatment arms in a randomized fashion to compare tolerability and safety. Population PK parameters, clinical activity, durability of response and safety of GSK2118436 and GSK1120212 dosed orally in combination and GSK2118436 as monotherapy were evaluated. Part D consisted of evaluation of the pharmacokinetics of GSK2118436 HPMC capsules administered as monotherapy and in combination with GSK1120212. Pharmacokinetics of GSK2118436 was assessed following a single dose on Day 1 and after repeat dosing (Day 21) and compared between combination and monotherapy. The pharmacokinetics of GSK1120212 was also be assessed. Safety, tolerability and clinical activity were evaluated in 4 dosing cohorts. These cohorts might be expanded for additional safety data. Subjects were randomized to different cohorts.
Source references
references
  1. citation
    Flaherty KT, Infante JR, Daud A, Gonzalez R, Kefford RF, Sosman J, Hamid O, Schuchter L, Cebon J, Ibrahim N, Kudchadkar R, Burris HA 3rd, Falchook G, Algazi A, Lewis K, Long GV, Puzanov I, Lebowitz P, Singh A, Little S, Sun P, Allred A, Ouellet D, Kim KB, Patel K, Weber J. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med. 2012 Nov 1;367(18):1694-703. doi: 10.1056/NEJMoa1210093. Epub 2012 Sep 29.
    pmid
    23020132
    type
    BACKGROUND
  2. citation
    Long GV, Eroglu Z, Infante J, Patel S, Daud A, Johnson DB, Gonzalez R, Kefford R, Hamid O, Schuchter L, Cebon J, Sharfman W, McWilliams R, Sznol M, Redhu S, Gasal E, Mookerjee B, Weber J, Flaherty KT. Long-Term Outcomes in Patients With BRAF V600-Mutant Metastatic Melanoma Who Received Dabrafenib Combined With Trametinib. J Clin Oncol. 2018 Mar 1;36(7):667-673. doi: 10.1200/JCO.2017.74.1025. Epub 2017 Oct 9.
    pmid
    28991513
    type
    DERIVED
  3. citation
    Long GV, Grob JJ, Nathan P, Ribas A, Robert C, Schadendorf D, Lane SR, Mak C, Legenne P, Flaherty KT, Davies MA. Factors predictive of response, disease progression, and overall survival after dabrafenib and trametinib combination treatment: a pooled analysis of individual patient data from randomised trials. Lancet Oncol. 2016 Dec;17(12):1743-1754. doi: 10.1016/S1470-2045(16)30578-2. Epub 2016 Nov 16.
    pmid
    27864013
    type
    DERIVED
  4. citation
    Long GV, Weber JS, Infante JR, Kim KB, Daud A, Gonzalez R, Sosman JA, Hamid O, Schuchter L, Cebon J, Kefford RF, Lawrence D, Kudchadkar R, Burris HA 3rd, Falchook GS, Algazi A, Lewis K, Puzanov I, Ibrahim N, Sun P, Cunningham E, Kline AS, Del Buono H, McDowell DO, Patel K, Flaherty KT. Overall Survival and Durable Responses in Patients With BRAF V600-Mutant Metastatic Melanoma Receiving Dabrafenib Combined With Trametinib. J Clin Oncol. 2016 Mar 10;34(8):871-8. doi: 10.1200/JCO.2015.62.9345. Epub 2016 Jan 25.
    pmid
    26811525
    type
    DERIVED
  5. citation
    Corcoran RB, Atreya CE, Falchook GS, Kwak EL, Ryan DP, Bendell JC, Hamid O, Messersmith WA, Daud A, Kurzrock R, Pierobon M, Sun P, Cunningham E, Little S, Orford K, Motwani M, Bai Y, Patel K, Venook AP, Kopetz S. Combined BRAF and MEK Inhibition With Dabrafenib and Trametinib in BRAF V600-Mutant Colorectal Cancer. J Clin Oncol. 2015 Dec 1;33(34):4023-31. doi: 10.1200/JCO.2015.63.2471. Epub 2015 Sep 21.
    pmid
    26392102
    type
    DERIVED
  6. citation
    Latimer NR, Amonkar MM, Stapelkamp C, Sun P. Adjusting for confounding effects of treatment switching in a randomized phase II study of dabrafenib plus trametinib in BRAF V600+ metastatic melanoma. Melanoma Res. 2015 Dec;25(6):528-36. doi: 10.1097/CMR.0000000000000193.
    pmid
    26340744
    type
    DERIVED
  7. citation
    Johnson DB, Flaherty KT, Weber JS, Infante JR, Kim KB, Kefford RF, Hamid O, Schuchter L, Cebon J, Sharfman WH, McWilliams RR, Sznol M, Lawrence DP, Gibney GT, Burris HA 3rd, Falchook GS, Algazi A, Lewis K, Long GV, Patel K, Ibrahim N, Sun P, Little S, Cunningham E, Sosman JA, Daud A, Gonzalez R. Combined BRAF (Dabrafenib) and MEK inhibition (Trametinib) in patients with BRAFV600-mutant melanoma experiencing progression with single-agent BRAF inhibitor. J Clin Oncol. 2014 Nov 20;32(33):3697-704. doi: 10.1200/JCO.2014.57.3535. Epub 2014 Oct 6.
    pmid
    25287827
    type
    DERIVED
  8. citation
    Frederick DT, Salas Fragomeni RA, Schalck A, Ferreiro-Neira I, Hoff T, Cooper ZA, Haq R, Panka DJ, Kwong LN, Davies MA, Cusack JC, Flaherty KT, Fisher DE, Mier JW, Wargo JA, Sullivan RJ. Clinical profiling of BCL-2 family members in the setting of BRAF inhibition offers a rationale for targeting de novo resistance using BH3 mimetics. PLoS One. 2014 Jul 1;9(7):e101286. doi: 10.1371/journal.pone.0101286. eCollection 2014.
    pmid
    24983357
    type
    DERIVED
  9. citation
    Carlino MS, Gowrishankar K, Saunders CA, Pupo GM, Snoyman S, Zhang XD, Saw R, Becker TM, Kefford RF, Long GV, Rizos H. Antiproliferative effects of continued mitogen-activated protein kinase pathway inhibition following acquired resistance to BRAF and/or MEK inhibition in melanoma. Mol Cancer Ther. 2013 Jul;12(7):1332-42. doi: 10.1158/1535-7163.MCT-13-0011. Epub 2013 May 3.
    pmid
    23645591
    type
    DERIVED
Source notices and limitations
    Discovery and provenance
    1. release id
      ctgov-registry-7ad944f6deaf1f5cd6122126
      edge id
      nct-edge-b1278096847ed0cbbd7b
      requested nct id
      NCT01072175
      primary nct id
      NCT01072175
      source kind
      nci_explicit_reference_or_link
      source record id
      Source null
      source file sha256
      68c1706258e98d38c9ed48fd0c71432d06d320b05c8885ceb5fa728eadea7590
      payload sha256
      3aea7b8ff89dd78fbe8befe69c22e145fe6abe165c2806b67d88ff544859e78d
      payload
      clinical indication matching status
      not_inferred
      end exclusive
      true
      id
      nct-edge-b1278096847ed0cbbd7b
      link basis
      explicit_NCT_identifier_in_acquired_source
      nct id
      NCT01072175
      occurrences
      1. context exact
        d).[<a href="#cit/section_5.4">4</a>]</li></ul></div> <p id="_289" tabindex="-1">The approval was also supported by results from <a href="/clinicaltrials/NCT01072175">COMBI-d</a> (NCT01072175), <a href="/clinicaltrials/NCT01597908">COMBI-v</a> (NCT01597908), and <a href="/clinicaltrials/NCT01336634">BRF113928</a> (NCT013366
        end
        51050
        exact text
        NCT01072175
        start
        51039
      2. context exact
        5.4">4</a>]</li></ul></div> <p id="_289" tabindex="-1">The approval was also supported by results from <a href="/clinicaltrials/NCT01072175">COMBI-d</a> (NCT01072175), <a href="/clinicaltrials/NCT01597908">COMBI-v</a> (NCT01597908), and <a href="/clinicaltrials/NCT01336634">BRF113928</a> (NCT01336634).[<a href="#cit/section
        end
        51076
        exact text
        NCT01072175
        start
        51065
      offset unit
      unicode_code_points
      source file
      /tmp/cancer-full-research/nci/raw/673b6b58fe51113964.html
      source file sha256
      68c1706258e98d38c9ed48fd0c71432d06d320b05c8885ceb5fa728eadea7590
      source json pointer
      Source null
      source kind
      nci_explicit_reference_or_link
      source record id
      Source null
      source retrieved at
      2026-09-09T23:21:27.710469+00:00
      source string basis
      UTF-8_text_with_universal_newline_translation
      source string sha256
      dd1d1d1ad91100ad4c1f7e9f55ba1a72466b1757ab229115c118a2a0940b3724
      source title
      Agnostic Cancer Therapies (PDQ®)–Health Professional Version
      source update dates
      1. context
        Updated: February 12, 2025
        datetime
        2025-02-12T12:00:00Z
        display
        February 12, 2025

    Preserved source evidence · Independent clinical review pending · Not medical advice